IFN-β Restricts Tumor Growth and Sensitizes Alveolar Rhabdomyosarcoma to Ionizing Radiation

Sims, Thomas L.; McGee, Mackenzie; Williams, Regan F.; Myers, Adrianne L.; Tracey, Lorraine; Hamner, John B.; Ng, Catherine Y.; Wu, Jianrong; Gaber, M. Waleed; McCarville, M. Beth; Nathwani, Amit C.; Davidoff, Andrew M.

doi:10.1158/1535-7163.mct-09-0800

Cited by 13 publications

(17 citation statements)

References 35 publications

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“…Orthotopic intramuscular (IM) ARMS xenografts were established in male CB-17 severe combined immunodeficient mice (Taconic, Hudson, NY), as previously described [23]. The size of the IM tumors was estimated by measuring the volume of the normal left calf and subtracting that from the volume of the tumor-bearing right calf.…”

Section: Methodsmentioning

confidence: 99%

Curcumin Potentiates Rhabdomyosarcoma Radiosensitivity by Suppressing NF-κB Activity

et al. 2013

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Ionizing radiation (IR) is an essential component of therapy for alveolar rhabdomyosarcoma. Nuclear factor-kappaB (NF-κΒ) transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of curcumin, a putative NF-κΒ inhibitor, and cells expressing genetic NF- κΒ inhibitors (IκBα and p100 super-repressor constructs) to function as a radiosensitizer. Ionizing radiation induced NF-κΒ activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-κΒ target proteins. Pretreatment of the cells with curcumin inhibited radiation-induced NF-κΒ activity and target protein expression. In vivo, the combination of curcumin and IR had synergistic antitumor activity against Rh30 and Rh41 ARMS xenografts. The greatest effect occurred when tumor-bearing mice were treated with curcumin prior to IR. Immunohistochemistry revealed that combination therapy significantly decreased tumor cell proliferation and endothelial cell count, and increased tumor cell apoptosis. Stable expression of the super-repressor, SR-IκBα, that blocks the classical NF-κB pathway, increased sensitivity to IR, while expression of SR-p100, that blocks the alternative pathway, did not. Our results demonstrate that curcumin can potentiate the antitumor activity of IR in ARMS xenografts by suppressing a classical NF-κΒ activation pathway induced by ionizing radiation. These data support testing of curcumin as a radiosensitizer for the clinical treatment of alveolar rhabdomyosarcoma.Impact of workThe NF-κΒ protein complex has been linked to radioresistance in several cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-κΒ activity by either pharmacologic (curcumin) or genetic (SR-IκBα) means significantly enhanced the efficacy of radiation therapy in the treatment of alveolar rhabdomyosarcoma cells and xenografts. These data suggest that preventing the radiation-induced activation of the NF-κΒ pathway is a promising way to improve the antitumor efficacy of ionizing radiation and warrants clinical trials.

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Section: Methodsmentioning

confidence: 99%

Curcumin Potentiates Rhabdomyosarcoma Radiosensitivity by Suppressing NF-κB Activity

et al. 2013

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“…Because the newest class of anti-cancer agents, anti-angiogenic agents, alter tumor blood flow but may not substantially alter tumor size, CEUS is emerging as a promising modality for assessing response to these agents in adult cancers [20,21,34,35]. Our preclinical studies have shown that quantitation of US contrast agent flow into pediatric murine models of neuroblastoma and rhabdomyosarcoma allows accurate monitoring of changes in tumor blood flow induced by a variety of anti-angiogenic agents [22–24]. …”

Section: Discussionmentioning

confidence: 99%

Contrast-enhanced sonography of malignant pediatric abdominal and pelvic solid tumors: preliminary safety and feasibility data

et al. 2012

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Background Little information exists regarding pediatric contrast enhanced ultrasonography. Objective To assess the safety and feasibility of contrast enhanced ultrasonography of pediatric abdominal and pelvic tumors. Materials and Methods This prospective study included eight boys and five girls (mean age, 10.8 years) with abdominal or pelvic tumors. Cohorts of three subjects underwent ultrasound with perflutren contrast agent at escalating dose levels.Neurological and funduscopic examination, electrocardiography, and continuous pulse oximetry were performed before and after contrast administration. Threeradiologists independently scored six imaging parameters on pre- and post-contrast sonography. Inter-reviewer agreement was measured by the Kappa statistic. Results No neurological, retinal, electrocardiographic, or pulse oximetry changes were attributable to the contrast agent. Two subjects reported minor, transient symptoms. Post-contrast ultrasound parameter scores improved slightly in 8 of 12 subjects. Post-contrast ultrasound inter-reviewer agreement improved slightly for detection of tumor margins (pre-contrast = 0.20, post-contrast = 0.26), local tumor invasion (pre-contrast = −0.01, post-contrast = 0.10) and adenopathy (pre-contrast = 0.35, post-contrast = 0.44). Conclusions Although our sample size is small, perflutren contrast agents appear to be safe and well tolerated in children. Contrast enhanced sonography of pediatric abdominal and pelvic tumors is feasible but larger studies are needed to define their safety and efficacy in this patient population.

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“…Apoptosis in tumors was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling using a commercially available in situ apoptosis detection kit (Serologicals, Billerica, Massachusetts) as previously described 13 . Tumor cell proliferation was analyzed by staining formalin-fixed, paraffin-embedded sections (4 μm) with anti-Ki67 (rabbit monoclonal clone SP6; Neomarkers, Fremont, California).…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Liposome-encapsulated curcumin suppresses neuroblastoma growth through nuclear factor-kappa B inhibition

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Denbo²,

Saab³

et al. 2012

Surgery

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Background Nuclear factor-κB (NF-κB) has been implicated in tumor cell proliferation and survival, and tumor angiogenesis. We sought to evaluate the effects of curcumin, an inhibitor of NF-κB, on a xenograft model on disseminated neuroblastoma. Methods For in vitro studies, neuroblastoma cell lines, NB1691, CHLA-20, and SK-N-AS, were treated with varying doses of liposomal curcumin. Disseminated neuroblastoma was established in vivo by tail vein injection of NB1691-luc cells into SCID mice which were then treated with 50mg/kg/day of liposomal curcumin 5 days/week intraperitoneal. Results Curcumin suppressed NF-κB activation and proliferation of all neuroblastoma cell lines in vitro. In vivo, curcumin treatment resulted in a significant decrease in disseminated tumor burden. Curcumin treated tumors had decreased NF-κB activity and an associated significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis, as well as a decrease in tumor VEGF levels and microvessel density. Conclusions Liposomal curcumin suppressed neuroblastoma growth, with treated tumors showing a decrease in NF-kB activity. Our results suggest that liposomal curcumin maybe a viable option for the treatment of neuroblastoma that works via inhibiting the NF-κB pathway.

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IFN-β Restricts Tumor Growth and Sensitizes Alveolar Rhabdomyosarcoma to Ionizing Radiation

Cited by 13 publications

References 35 publications

Curcumin Potentiates Rhabdomyosarcoma Radiosensitivity by Suppressing NF-κB Activity

Curcumin Potentiates Rhabdomyosarcoma Radiosensitivity by Suppressing NF-κB Activity

Contrast-enhanced sonography of malignant pediatric abdominal and pelvic solid tumors: preliminary safety and feasibility data

RETRACTED: Liposome-encapsulated curcumin suppresses neuroblastoma growth through nuclear factor-kappa B inhibition

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